Lupus and Kidney

Naheed Ansari, MD FASN10/15/12

Systemic Lupus Erythematosis

• The term “Lupus Erythematosis” was introduced in 19th century to describe skin lesions

• 100 years later, it was realized that it is a systemic disease and it is causes by some aberrant autoimmunity

• Prevalence- 1 case per 2000 population• Currently, US 322,000 have SLE• Incidence higher in African Americans,Hispanics,

and Asian ancestry• 4 year survival rate- 50% in 1950s• 15 year survival rate- 80% in 2012

Lupus Nephritis

• Multisystem involvement• Lupus patients are more at risk for development of

kidney disease than people who do not have lupus• Kidney involvement can occur in upto 50% of patients

with SLE. It usually occurs within first 5 years of diagnosis of SLE.

• Renal involvement can occur before ACR criterion for SLE is made

• Patients with SLE can also develop kidney disease due to other medical problems like Diabetes Mellitus

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Lupus Nephritis

• Defined as presence of abnormal elements in the urine of patients with SLE

• red blood cells, white blood cells• Red blood cell casts in urine

• Presence of protein >0.5gm/Day• Elevated serum creatinine reflecting kidney

damage• occurs both in children and • adults

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Lupus Nephritis

Cameron et al:JASN 1999

Lupus Nephritis- Clinical Features

• History: • Patients usually experience other symptoms of active

SLE like rash, fatique, arthritis,serositis or clinical CNS disease

• Some patients are asymptomatic usually with mesangial/membranous lupus nephritis.

• Some patients experience swelling of the body due to proteinuria. Some are hypertensive along with proteinuria.

• Some have symptoms associated with hypertension like dizziness,headaches and heart failure

Lupus Nephritis- Clinical Features

• Physical Examination: • Evidence of rash, oral or nasal ulcers, joint swelling,

brown or foamy urine and changes in amount of urine

• Patients with active lupus nephritis have hypertension, peripheral edema, and occasionally heart failure

• With membranous nephropathy, signs of nephrotic syndrome( peripheral edema, ascites, pericardial effusion and pleural effusions can be seen.

Diagnosis of Lupus Nephritis

• Blood tests» BUN » Serum Creatinine» Laboratory tests for lupus disease activity like complement

level, antibodies to DNA, ESR,CRP etc

• Urine tests» Urinalysis- presence of blood or protein in the urine as well

as presence of red blood cell casts» Spot urine for protein/creatinine ratio» 24 hour urine for creatinine clearance and protein

• Kidney biopsy

International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003

classification of lupus nephritis• Class I Minimal mesangial lupus nephritis• Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence

• Class II Mesangial proliferative lupus nephritis• Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial

immune deposits

• Class III Focal lupus nephritis• Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all

glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations– A=active lesions, C=chronic lesions

• Class IV Diffuse lupus nephritis• Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving >50% of all

glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations.– This class is divided into diffuse segmental(IV-S) lupus nephritis when 50% of the involved glomeruli have segmental lesions, and diffuse

global (IV-G) lupus nephritis when 50% of the involved glomeruli have global lesions.– A=active lesions, C=chronic lesions

• Class V Membranous lupus nephritis• Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by

immunofluorescence or electron microscopy, with or without mesangial alterations– Class V lupus nephritis may occur in combination with class III or IV in which case both will be diagnosed

Lupus Nephritis- Biopsy Findings

Norma Kidney- Light Micro

Mesangioproliferative Lupus Nephritis

Lupus Nephritis( Biopsy Findings)

Proliferative GN with necrosis Cellular Crescent

Lupus Nephritis

Lupus Membranous- LM Lupus Membranous- EM

Lupus Nephritis

Lupus Podocytopathy-LM Lupus Podocytopathy- EM

IgG vessel wall depositsIgG-TBM deposits

IF staining for IgG

US NIH renal Pathology System for Lupus Nephritis

Treatment of Lupus Nephritis• Depends upon class of LN diagnosed on kidney biopsy along with

presence of extra-renal manifestations of SLE

• Goal of treatment is to normalize kidney function, reduce proteinuria, and prevent progressive loss of kidney function.

• Conservative (Non-immunomodulatory) treatment is appropriate for Class I and II LN

• RAAS Blockade with ACE/ARB delays progression of Lupus Nephritis• (Durán-Barragán S et al. Rheumatology 2008;47:1093-1096)

• Spironolactone significantly reduces proteinuria and lowers levels of anti ds DNA and anti ss DNA

• (Role of aldosterone blockade in murine lupus nephritis Arthritis Res Ther 2008;10:R5)

Kaplan–Meier survival curve for the development of renal involvement as a function of the use of ACE inhibitors.

Durán-Barragán S et al. Rheumatology 2008;47:1093-1096

Treatment of Lupus Nephritis

• Patients with proliferative classes of lupus nephritis need immunomodulatory treatment to turn off the immune system.

• Induction: usually Corticosteroids with either Cyclophosphamide or Mycophenalate are used for first six months

• Maintenance: usually with lowest and best tolerated immunosuppressive medication. Azathioprine or Mycophenalate are used based on recent clinical trials

Induction Treatment

• It is initial intense treatment given to induce remission of active disease

• Corticosteroids» PO or IV» 3 day Pulse( 7mg/kg/day) followed by 1mg/kg/day ( not

exceeding 60mg/day) for 8 weeks and then taper» Glucocorticoids alone is significantly less effective

• Immunosuppressive agents» Cyclophosphamide (Cytoxan) given IV » Mycophenalate Mofetil (cellcept) administered orally » Azathioprine( Imuran)

Cyclophosphamide

• Efficacious when used in conjunction with glucocorticoids

• can be used intravenously or orally• Used in dose of 0.5- 1.0gm/m2 monthly for six

months and then quarterly for at least two years

• Can be given in biweekly doses of 500mg/m2• Toxicity remains an issue

Methylprednisolone and cyclophosphamide Alone or in Combination in Patients w LN

• Randomized Controlled Trial in 85 Pts

• Treatment Remission • IV Cyt x 6 mo + q 3rd mo 13/21 62%• Methylpred 1 g/m2 x 1yr 7/24 29%• Combined Therapy 17/20 85%

• Gourly MF, et al. Ann Int Med. 125:549, 1996

Standard “NIH protocol” dosing

Kaplan-Meier Analysis of Failure of Therapy

0.9

0.8

0.7

0.6

0.5

0.4

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0.2

0 24 48 72 96 120Months From Study Entry

Pro

babili

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py

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00 2424 4848 7272 9696

Cy + MPCy alone

272827

252723

252723

242619

232317

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182011

182010

171710

1115

712

68

CyCy + MPMP

Patients at Risk

1.0

MP alone

Illei GG, et al. Ann Intern Med. 2 001

Long-term Follow-up of Protocol Completers in WHO Class IV LN

MP + CY(n = 20)

MP alone(n = 24*)

CY alone(n = 21)

*14 of 24 patients received CY after study completion

Illei GG, et al. Ann Intern Med. 2001;135:248-257.

Pati

ents

(%

)

50

40

30

20

10

0

50% Rise SCr

Doubling SCr

Dialysis

• Multicenter Prospective Clinical trial

• Enrolled 90 patients from September 1996 – 2000 in 19 European centers

• Objective: To evaluate efficacy and safety of low dose IV CYC for remission induction followed by AZA

90 Patients with LN Class III-V

High Dose IV CYC46

(6 monthly pulses and 2 quaterly pulses)

40 Remained in the study

Low Dose IV CYC44

(6 pulses of 500mg q2wks)

38 Remained in the study

Euro Lupus Trial- Study Design

Euro Lupus TrialEuro Lupus Trial Treatment failure

Free o

f Fa

ilure

(%

) LD

0 12 24 36 48 60

Follow-up (months)

50

60

70

80

90

100

0

LDHD

HD

Houssiau Houssiau et alet al., Arthritis Rheum, 2002., Arthritis Rheum, 2002

Mycophenalate Mofetil- Cellcept

Group 1: MMF Group 1: MMF (2 g x 6 mo, (2 g x 6 mo, then 1 g x 6 then 1 g x 6 mo) + mo) + prednisone prednisone (0.8 mg/kg)(0.8 mg/kg)

Group 2: POCY Group 2: POCY (2.5 mg/kg/d (2.5 mg/kg/d x 6 mo), thenx 6 mo), thenAZA (1.5-2.0 AZA (1.5-2.0 mg/kg/d) + mg/kg/d) + prednisoneprednisone

Efficacy of MMF vs sequential PO CYT-AZA in 42 Efficacy of MMF vs sequential PO CYT-AZA in 42 patients with DPLNpatients with DPLN

Chan TM et al. Chan TM et al. New Engl J MedNew Engl J Med 2000; 343:1156-62. 2000; 343:1156-62.

Pts (%)Pts (%)

Multicenter Trial of MMF vs IV CTX for Induction Therapy of Severe LN

• Multicenter, randomized, non-blinded trial of induction RX for severe active LN

• Designed as equivalence trial• Calculated sample size: 64/ Rx arm

• Hypothesis: MMF has equivalent efficacy with superior toxicity/tolerability profile vs. IVC

• • Ginzler et al. N Eng J Med 2005

Baseline Patient Characteristics

MMF (n=71)

IVC (n=69)

Age ( yrs) 32.5 ± 10.0 31.0 ± 9.0Female 61 (86%) 65 (94%)Black 43 (61%) 36 (52%)Duration of SLE, mo. 43.72 ±

66.8858.70 ± 80.64

Screatinine, mg/dL 1.06 ± 0.52 1.08 ± 0.49Urine protein, g/24 hr 4.06 ± 3.14 4.41 ± 3.51Urine sediment

RBC/hpfWBC/hpf

24.1 ± 50.312.6 ± 23.5

33.2 ± 115.510.3 ± 17.3

Salbumin, g/L 2.81 ± 0.95 2.69 ± 0.56

Remission Rates: MMF vs. IVCIntent to treat analysis

P=NSP=0.005

P=0.009

Perc

ent

Resp

ond

ing

• Multinational, Prospective, Randomized, Open label trial comparing

MMF to IV Cyclophosphamide

• Background: Smaller studies have shown that MMF may offer advantages over IV Cyclophosphamide for treatment of Lupus Nephritis but there is no large International Randomized control trial

• Objective: To assess the efficacy and safety of MMF as Induction therapy in Lupus Nephritis

• Hypothesis: More patents with Lupus Nephritis would respond to MMF than IV Cyclophosphamide during 24 weeks

Randomized (n = 370)Open-label treatment

Allocated to MMF (n = 185)

Received MMF (n = 184)

Withdrawals (n = 35) Due to adverse event (n = 24)

Consent withdrawn (n = 6)Other reason (n = 5)

Allocated to IVC (n = 185)

Received IVC (n = 180)

Withdrawals (n = 29) Due to adverse event (n = 13)

Consent withdrawn (n = 5)Other reason (n = 11)

Maintenance phase Double-blind re-randomization to corticosteroids plus MMF or azathioprine for up to 3 years

Primary endpoint: responders in randomized population (n = 370)

Responders

MMF IVC

ALMS TRIAL – RCT MMF vs IVC in Severe LN Appel , Contreras, Dooley et al JASN 2009

Appel, G. B. et al. J Am Soc Nephrol 2009;20:1103-1112

Figure 2. Response rates of study population and by racial group

Summary – Induction Phase Therapy for Class III or IV LN

• Multiple options– Standard, NIH protocol IV CTX

• 0.75-1.0 g/m2 IV q4 weeks for 6 doses– Eurolupus IV CTX

• 500 mg IV q2 weeks for 6 doses– MMF

• 2000-3000 mg/day for 6 months• All should be given alongside standard steroid

regimen– 3 days pulse (7 mg/kg) followed by PO steroids at 1

mg/kg/day (not exceeding 60 mg) for 8 weeks, then taper

Treatment of Resistant LN • Some patients are challenging for induction• Plasmaphresis may be beneficial in some cases although randomized

controlled trials showed no benefit• Tacrolimus can by used

• Rituximab - FDA approved for the treatment of relapsed or refractory, CD20-positive B-cell NH Lymphomas and Rheumatoid Arthritis

• Chimeric murine/human monoclonal antibody• Used in many glomerular diseases in uncontrolled trials• LUNAR study showed that induction of complete or partial

remission is higher with rituximab as compared to placebo

Rovin et al LUNAR study Arth Rheu 2012Lewis et al NEJM 1992Euler et al Arth Rheum 1994

Maintenance Therapy for Proliferative LN

• Up to 50% of patients with LN relapse during reduction in or cessation of immunosuppressive therapy

• Relapse rate is 5-15 per 100 patient years with an average of 8 per 100 patient years for first 5 years of follow up.

• Treatment is usually continued for 24 months to prevent progressive kidney disease• Usually treatment with cellcept or azathioprine is continued to keep patient in

remission and prevent relapses• Cyclosporine is not used due to high risk of relapse upon withdrawl of drug• Low dose oral prednisone is continued in most patients receiving maintenance

therapy with goal to prevent extrarenal symptoms. Usually a dose of 0.05 to 0.2mg/kg/day is used

Houssiau et al Maintain Trial 2010Chan et al JASN 2005Contreras et al NEJM 2004

Treatment of LN- Membranous Nephropathy

• Treatment with immunosuppressive drugs is indicated in patients» Severe symptomatic nephrotic syndrome» Rising serum creatinine» Mixed membranous and proliferative lesions on renal biospy» Non immunosuppressive treatment is continued in these patients along with

immunosuppressive drugs

• Various drugs can be used in patients with class V lupus nephritis, usually Mycophenalate is used for remission of nephrotic syndrome because of its safety and better tolerance.

• • IV cyclophosphamide and cyclosporine can be used as alternative

when MMF cannot be used.

• Non immunosuppressive agents include use of ACEI, statins, aspirin, non dihydropyridine calcium channel blockers

Partial and Complete Remission RatesMembranous LN

Radhakrishnan J, Moutzouris D, Ginzler E, and Appel GB Kidney Int 77:152-160, 2009.

Prognostic Features- Lupus Nephritis

• End Stage Renal Disease can occur in some patients with lupus• Histological Predictors• Class IV (diffuse proliferative LN)• High activity and chronicity on Biopsy• Crescents• Interstitial fibrosis• Segmental necrotizing lesions• Clinical Predictors• Hypertension• Anemia• High baseline serum creatinine • Higher baseline proteinuria• Delay in therapy• Epidemiologic Predictors• African American Race• Low socioeconomic status

Treatment of LN- ESRD

• Survival rate for individuals with LN after 10 years of diagnosis of SLE is reduced to 88%.

• This survival rate is further reduced in African Americans• 15-20% of patients with lupus nephritis start renal replacement

therapy if End Stage Renal Disease occurs• USRDS data shows that 1.4% of ESRD due to LN

» Hemodialysis» Peritoneal Dialysis» Kidney Transplantation

Appel et al: AJKD 1987: 83-877Ortega LM et al: Lupus 2010: 19-557

Hemodialysis• Patient survival with either hemodialysis or CAPD appears to be

similar in patients with ESRD ( 5 year survival rate is 90%)• Most lupus nephritis patients with end-stage renal disease opt for

hemodialysis therapy(82%)• Increased risk of death during the first three months of dialysis due

to sepsis and other complications of high dose of steroids.

Cheigh et al AJKD 1993: 21:2Devlin et al Arth Care & Resear 2011

Peritoneal Dialysis• Peritoneal dialysis and kidney transplantations lower among

African-Americans, uninsured, and unemployed• Only 12.2% of LN patients started PD between 1995-2006

• Patients on PD do better than HD after kidney transplantation

• There may be high risk of peritonitis and non catheter related Infections in PD.

Huang et al PDI 2001 21:143Siu YP et al NDT 2005 20:2797Kasiske et al J Transp 2001

Kidney Transplantation• Under utilized in patients with LN• Only 3% of LN patients undergo renal transplantation• Graft survival rates at 5 and 10 years in patients with lupus are similar to those in

patients with other diseases.• Rate of recurrent disease is low ( 2-9% in LN patients)• Patients with rapidly progressive renal disease • Should undergo dialysis before kidney transplant• Measurement of serologic marker such as titres of • DNA and complement levels do not help predict • disease recurrence• Kidney transplant recipients with lupus and • Antiphospholipid antibodies are at increased • Risk for thrombotic events.

Stone et al Semin Arth Rheu 1997Choy et al Am J Transplant 2006

Thank You